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Simvastatin Inhibits Airway Hyperreactivity

Implications for the Mevalonate Pathway and Beyond

¹ Center for Comparative Respiratory Biology and Medicine, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of California Davis, Davis, California

Correspondence and requests for reprints should be addressed to Nicholas J. Kenyon, M.D., University of California, Davis Genome and Biomedical Sciences Facility (GBSF), 451 Health Sciences Drive, Room 6517, Davis, CA 95616. E-mail: njkenyon{at}ucdavis.edu

Rationale: Statin use has been linked to improved lung health in asthma and chronic obstructive pulmonary disease. We hypothesize that statins inhibit allergic airway inflammation and reduce airway hyperreactivity via a mevalonate-dependent mechanism.

Objectives: To determine whether simvastatin attenuates airway inflammation and improves lung physiology by mevalonate pathway inhibition.

Methods: BALB/c mice were sensitized to ovalbumin over 4 weeks and exposed to 1% ovalbumin aerosol over 2 weeks. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) was injected intraperitoneally before each ovalbumin exposure.

Measurements and Main Results: Simvastatin reduced total lung lavage leukocytes, eosinophils, and macrophages (P < 0.05) in the ovalbumin-exposed mice. Cotreatment with mevalonate, in addition to simvastatin, reversed the antiinflammatory effects seen with simvastatin alone (P < 0.05). Lung lavage IL-4, IL-13, and tumor necrosis factor- levels were all reduced by treatment with simvastatin (P < 0.05). Simvastatin treatment before methacholine bronchial challenge increased lung compliance and reduced airway hyperreactivity (P = 0.0001).

Conclusions: Simvastatin attenuates allergic airway inflammation, inhibits key helper T cell type 1 and 2 chemokines, and improves lung physiology in a mouse model of asthma. The mevalonate pathway appears to modulate allergic airway inflammation, while the beneficial effects of simvastatin on lung compliance and airway hyperreactivity may be independent of the mevalonate pathway. Simvastatin and similar agents that modulate the mevalonate pathway may prove to be treatments for inflammatory airway diseases, such as asthma.

Key Words: statin • asthma • physiology • HMG-CoA reductase • small G protein

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The statin drugs have pleiotropic immune modulatory properties beyond their lipid-lowering effects. Reports indicate that the statin drugs may have beneficial effects on lung health including asthma and chronic obstructive pulmonary disease. The mechanisms of this observed benefit in the lung are not yet clear. What This Study Adds to the Field Bronchial influx of inflammatory cells in allergic lung disease occurs via a mevalonate-dependent pathway. Improvements in lung physiology after simvastatin treatment may occur via mevalonate-independent pathways, and are likely due to effects predominantly on resident airway cells rather than inflammatory cells.